Low-solubility drugs often show poor bioavailability or irregular absorption, the degree of irregularity being affected by factors such as dose level, fed state of the patient, and form of the drug. Increasing the bioavailability of low-solubility drugs has been the subject of much research. Increasing bioavailability hinges on improving the concentration of the drug in solution to improve absorption.
It is known that many low-solubility drugs can be formulated so as to increase the maximum concentration of the drug that will dissolve in an aqueous solution in in-vitro tests. It has been shown that when such forms are tested in vivo they can enhance the relative bioavailability of the drug, presumably by enhancing, at least temporarily, the concentration of dissolved drug present in the gastrointestinal (GI) tract.
Another approach is that some low-solubility drugs may be formulated in highly soluble salt forms that provide temporary improvements in the concentration of the drug in a use environment relative to another salt form of the drug. An example of such a drug is sertraline, which in the lactate salt form has a higher aqueous solubility at pH 3 than the HCl salt form. Use of water soluble acid addition salt of poorly soluble drug is disclosed in U.S. Pat. No. 5,441,747.
It is known that other drug form known to provide, increased concentrations in solution of low-solubility drugs consists of drug in a hydrate or solvate crystalline form of the drug. Such forms often have higher aqueous solubility relative to the lowest solubility crystalline form and, therefore, provide higher concentrations of drug. Polymorphs comprise another drug form that temporarily provides increased concentrations in solution. Some polymorphs, also referred to herein as “high-energy crystalline forms,” have higher aqueous solubility and therefore can provide enhanced aqueous concentration of the drug relative to other crystal structures and relative to the equilibrium concentration.
It is also well known that the amorphous form of a low-solubility drug that is capable of existing in either the crystalline or amorphous form may also temporarily provide a greater aqueous concentration of drug relative to the equilibrium concentration of drug in a use environment. It is believed that the amorphous form of the drug dissolves more rapidly than the crystalline form, often dissolving faster than the drug can precipitate from solution. As a result, the amorphous form may temporarily provide a greater-than equilibrium concentration of drug.
Another method that can temporarily provide a greater than equilibrium drug concentration is to include a solubilizing agent such as citric acid, etc. in the drug form. Such solubilizing agents promote the aqueous solubility of the drug. An example of the use of a solubilizing agent with a drug to increase aqueous solubility is the use of solubilizing agents with sertraline. As disclosed in PCT Application No. 99/01120, when sertraline is co dissolved in aqueous solution with a solubilizing agent, for example, citric acid, the solubility of sertraline is dramatically increased.
Yet another technique for temporarily achieving a greater than equilibrium concentration of drug in a use environment is to formulate the drug as an aqueous or organic solution. For example, drug can be dissolved in polyethylene glycol (PEG) or an aqueous solution of PEG to which an acid or base may be added or the drug may be dissolved in an aqueous solution of an acid or base. Alternatively, the drug can be dissolved in a pharmaceutically acceptable organic liquid such as glycerol, mono-, di-, or triglycerides, fats or oils.
Another approach to increase the bioavailability of low-solubility drugs has involved forming amorphous dispersions of drugs with polymers. Examples of attempts to increase drug concentration by forming a dispersion of the drug with a polymer include Lahr et al., U.S. Pat. No. 5,368,864, Kanikanti et al., U.S. Pat. No. 5,707,655 and Nakamichi et al., U.S. Pat. No. 5,456,923. However, creating an amorphous dispersion of a drug and polymer(s) does have some drawbacks. For example, some drugs may degrade at the elevated temperatures used to form some dispersions. Some processes use organic solvents, which must be thoroughly removed to avoid drug degradation.
Increasing drug solubilization by using combinations of drug and polymer has also been described. For example, Martin et al., U.S. Pat. No. 4,344,934 mixed poorly-soluble drugs with polymers such as hydroxypropyl methyl cellulose (HPMC) and added an aqueous surfactant solution to the drug-polymer mixture. While this results in improved dissolution, there is only slight enhancement of drug concentration relative to the equilibrium concentration. Particle size reduction of active principle may also improve the bioavailabilty.
It is desirable that active pharmaceutical ingredient is released from the oral composition as soon as possible after ingesting it. This can normally be achieved by using a solublisation enhancing agent in the pharmaceutical composition. The solublisation enhancing agent may be a disintegrant, surface active agent or any other agents that enhance the solublisation. There is vast selection of different solublisation enhancing agents, including disintegrants, on the market, which have different chemical and physical characteristics. When selecting the best solublisation enhancing agent to be used in the pharmaceutical composition in combination with active agent, numerous factors have to be considered, e.g. the chemical and physical characteristics of the active agents, and solublisation enhancing agent, the chemical and physical characteristics of the auxiliary agents, such as diluents and binder, the method of preparing the composition, etc.
Various compound containing catechol moiety like entacapone, nitecapone, tolcapone or a pharmaceutically acceptable salt thereof, are used as active pharmaceutical ingredient are practically insoluble in water. Because of this property, dissolution of the product & bioavailability is always a challenge to develop the product in formulation.
Entacapone is an inhibitor of catechol-O-methyltransferase (COMT), used in the treatment of Parkinson's Disease as an adjunct to levodopa/carbidopa therapy.
Formulations of solid medicinal forms with the active ingredient entacapone, nitecapone or pharmaceutically acceptable salts thereof have already been described in U.S. Pat. No. 6,599,530. It was found that croscarmellose sodium can be used in an amount of at least 6% by weight of the composition to resolve the poor dissolution of entacapone, nitecapone or pharmaceutically acceptable salts thereof. Croscarmellose sodium is required for satisfactory dissolution as compared to other common dissolution-improving agents such as sodium lauryl sulphate, sodium starch glycolate, starch, pregelatinized starch, microcrystalline cellulose or mannitol. According to this invention, the poor dissolution problem of entacapone can be resolved by using croscarmellose sodium in an amount of at least 6% by weight of the composition. This patent justifies use of croscarmellose sodium in the marketed product.
Entacapone Tablet is available in US and elsewhere under the trade name of COMTAN®
The inactive ingredients of the COMTAN® Tablet are microcrystalline cellulose, mannitol, croscarmellose sodium, hydrogenated vegetable oil, hydroxypropyl methylcellulose, polysorbate 80, glycerol 85%, sucrose, magnesium stearate, yellow iron oxide, red oxide, and titanium dioxide. Physician's Desk Reference, 59th ed., pp. 2291-2295 (2005)